Latent sensitization: a model for stress-sensitive chronic pain

Abstract

Latent sensitization is a rodent model of chronic pain that reproduces both its episodic nature and its sensitivity to stress. It is triggered by a wide variety of injuries ranging from injection of inflammatory agents to nerve damage. It follows a characteristic time course in which a hyperalgesic phase is followed by a phase of remission. The hyperalgesic phase lasts between a few days to several months, depending on the triggering injury. Injection of μ-opioid receptor inverse agonists (e.g., naloxone or naltrexone) during the remission phase induces reinstatement of hyperalgesia. This indicates that the remission phase does not represent a return to the normal state, but rather an altered state in which hyperalgesia is masked by constitutive activity of opioid receptors. Importantly, stress also triggers reinstatement. Here we describe in detail procedures for inducing and following latent sensitization in its different phases in rats and mice.

Keywords: chronic pain; constitutive activity; hyperalgesia; latent sensitization; neuropathic pain; opioid receptor; stress.

Figure 1. Diagram of the phases of LS

1) Tissue injury leads from the normal state into a period of hyperalgesia. 2) Pain subsides into a remission phase. 3) An injection of opioid inverse agonist (naltrexone, NTX) produces a temporary reinstatement of the hyperalgesia.

Figure 2

Acrylic enclosure for paw withdrawal responses to von Frey filaments in mice.

Figure 3. Sample scoring sheet for the Up-and-Down method

Examples of the responses of 8 different mice. ‘X’ represents a paw withdrawal response and ‘O’ failure to respond. Numbers in parentheses are Log₁₀ [10*Force (mg)]. Final ‘50% Threshold’ values were calculated using the algorithm in (Chaplan et al., 1994).

Figure 4

Injection of CFA in the hind paw of a mouse.

Figure 5. Representative experiment showing CFA-induced LS in rats

A. Rats (n=13) received an injection of CFA (50 μl, s.c.) in one hindpaw. Mechanical hypersensitivity, measured with von Frey hairs, developed ipsilaterally and resolved by day 28. Two-way ANOVA: p<0.0001 for time, side and interaction, p=0.0002 for subject matching. B. On day 30, six of the rats were injected with naltrexone (NTX, 1 mg/kg s.c.), which resulted in reinstatement of hypersensitivity lasting ~1 hr. Two-way ANOVA: p<0.0001 for time and subject matching, p=0.96 for side, p=0.65 for interaction. Holm-Sidak’s post-hoc tests: * p<0.05, ** p<0.01, *** p<0.001.